Subtractive proteo-genomics and model-based druggability analyses prioritized nitrate reductase-A subunit-α as
Kainat Begum1, Sara Aiman2, Asifullah Khan3
1Department of Biochemistry, Abdul Wali Khan University Mardan (AWKUM), Mardan, 23200, Pakistan.
Background:
Bacterial pneumonia is a severe respiratory infection that damages the lungs, representing one of the most serious public health problems worldwide due to its morbidity and mortality across all age groups. The challenge is further exacerbated by emergence of multidrug-resistant strains of Streptococcus pneumoniae, Staphylococcus aureus, Klebsiella pneumoniae, and Haemophilus influenzae, making pneumonia treatment increasingly difficult due to the persistent spread of antimicrobial resistance. Consequently, it is crucial to explore novel therapeutic targets to treat multidrug-resistant pneumonia.
Results:
The current study is based on comprehensive analyses of proteo-genomics data from multidrug-resistant leading pneumonia pathogens. Its aim is to identify promising alternative anti-pneumonia drug targets. The analyses have identified 21 druggable targets enriched in pathogen-specific essential metabolic pathways, showing significant druggable potential. Among these, the nitrate reductase-A subunit-α have been prioritized as a new drug target, as there were no literature reports available about its druggability potential. Downstream analyses, including molecular docking, molecular dynamics simulations, virtual screening, and ADME analyses, predicted several potent druggable inhibitors against nitrate reductase-A subunit-α. Notably, aripiprazole and mirabegron, both established drugs from the DrugRep resource, were predicted as lead inhibitors of nitrate reductase-A subunit-α.
Conclusion:
The current study prioritizes several druggable targets against MDR pneumonia, including the nitrate reductase-A subunit-α as a potential alternative target for developing novel anti-pneumonia therapies.
Insights
Researchers identified novel drug targets for multidrug-resistant pneumonia by analyzing pathogen proteogenomics. Nitrate reductase-A subunit-α emerged as a promising target, with existing drugs showing potential inhibitory effects.
Area of Science:
- Microbiology and Infectious Diseases
- Drug Discovery and Development
- Computational Biology
Background:
- Bacterial pneumonia poses a significant global health threat, with increasing mortality and morbidity.
- The rise of multidrug-resistant (MDR) pathogens like Streptococcus pneumoniae complicates treatment options.
- Antimicrobial resistance necessitates the urgent identification of novel therapeutic targets for pneumonia.
Purpose of the Study:
- To identify novel druggable targets for combating multidrug-resistant pneumonia pathogens.
- To explore alternative therapeutic strategies beyond conventional antibiotics.
Main Methods:
- Proteogenomic data analysis of leading MDR pneumonia pathogens.
- Identification of essential metabolic pathways and druggable targets.
- Prioritization of novel targets, including nitrate reductase-A subunit-α.
- In silico validation using molecular docking, simulations, virtual screening, and ADME analyses.
Main Results:
- Identified 21 druggable targets within pathogen-specific metabolic pathways.
- Prioritized nitrate reductase-A subunit-α as a novel drug target due to its underexplored druggability.
- Predicted aripiprazole and mirabegron as potential lead inhibitors for nitrate reductase-A subunit-α.
Conclusions:
- The study highlights several druggable targets for MDR pneumonia.
- Nitrate reductase-A subunit-α is proposed as a viable alternative target for novel anti-pneumonia drug development.
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